The T cell receptor (TCR) complex consists of the clonotypic TCRα and β chains and the invariant CD3 γ, δ, ε and ζ chains, which are assembled in the endoplasmic reticulum and transported to the cell surface.
In various chronic pathologies such as cancer, autoimmune disorders and infectious diseases, partial or severe T lymphocyte and Natural Killer (NK) cell dysfunctions associated with a bystander down regulation of the ζ chain (CD247) was reported (reviewed in [1]). ζ chain is expressed in both T lymphocytes and NK cells as part of the T cell antigen receptor (TCR) and NK cytotoxic receptors (NCRs), respectively. In both cell types, the ζ chain has a key role in receptor assembly, expression and signaling function. The in vivo immunological mechanism underlying this phenomenon, which is observed as noted above in various diseases that largely differ in their etiology and physiology, was recently explored. It was shown that chronic inflammation is responsible for the induction of the bystander T and NK cell dysfunctions associated with ζ chain down regulation (2, 3 and 4). These studies revealed that low levels of ζ chain expression directly correlate with a chronic inflammation-dependent immunosuppressive environment. ζ chain down-regulation is not detected during acute inflammation. Moreover, elimination of the stimulus inducing the chronic inflammatory response leads to the recovery of ζ expression to normal levels.
Thus, ζ down regulation is a reversible event that depends upon the duration and severity of the inflammatory response. Our cumulative data led us to suggest that ζ chain down regulation could serve as a biomarker distinguishing between acute and chronic inflammation in patients suffering from diseases characterized by chronic inflammation and detects the ensuing immunosuppression. Moreover, due to its characteristics ζ chain could serve as a biomarker for detecting the patient's immune status; an immunosuppressive immune system and its recovery, upon a given treatment that will induce neutralization of the immunosuppressive environment and thus, recovery of the immune function.
WO05025310 describes the use of ζ chain expression level as a marker for an immunosuppressive environment, wherein down regulation of TCR ζ chain expression indicates the presence of an immunosuppressive environment. This application mentions the immunosuppressive environment as being indicative of one of the following conditions: chronic inflammation, cancer, infections and autoimmune disorders. This application also mentions the use of ζ chain expression as a prognostic marker for the emergence of an immunosuppressive environment (as a predictive biomarker) for predicting the immune status in any of the above-mentioned conditions.
Various studies reported the detection of zeta chain expression in autoimmune disease patients or in cancer patients (6, 7) using either isolated T-cells or PBLs isolated on Ficoll gradient. In such samples T cells are isolated from the original immunosuppressive cells in the environment that could lead to zeta chain recovery and gain of immune function. Eleftheriadis et al (5) showed that zeta chain expression is downregulated in hemodialysis patients (HD) as compared to healthy subjects. In this study although both diabetic and non-diabetic HD patients were studied, the study emphasized the effects of HD on zeta chain expression and did not suggest involvement of zeta chain downregulation in non-HD diabetic patients.
The metabolic system and the immune system are among the most fundamental systems required for survival. Many metabolic and immune response pathways or nutrient- and pathogen-sensing systems have been evolutionarily conserved throughout species. As a result, immune response and metabolic regulation are highly integrated and the proper function of each is dependent on the other. This interface can be viewed as a central homeostatic mechanism, dysfunction of which can lead to a cluster of chronic metabolic disorders characterized by chronic inflammation, particularly obesity, diabetes and cardiovascular disease (8). Collectively, the risks and complications of these diseases constitute the greatest current threat to global human health and welfare.
Diabetes mellitus comprises a group of diseases that manifest hyperglycemia associated with end organ complications (9). Up to date, no linkage between chronic inflammation-induced immunosuppression and complication appearance in diabetes was made.
One of the major medical problems today of patients suffering from diabetes is the inability to predict complications prior to their diagnosis and there is a lack in parameters measuring competency of a given therapy. Currently, inflammation measurements rely mainly on CRP levels, blood sedimentation rates and levels of pro-inflammatory cytokines. However, since these compounds are elevated under both acute and chronic inflammation, neither of them can uniquely point at a chronic inflammatory state and therefore, most complications of diabetes patients are diagnosed only upon their occurrence (10, 11).